Osteoarthritis (OA) affects 40 million people in the United States and is the leading cause of disability among persons older than 65 years. Currently, there is no form of medical or surgical therapy that can prevent, delay the onset, or affect the progression of this disease. Recent human epidemiologic data suggest that the incidence and progression of OA of the knee is lower in women who have taken estrogen replacement therapy (ERT). The overall objective of this proposal is to obtain additional data, from an appropriate animal model of naturally occurring OA and from in vitro studies, to determine the potential for ERT as an intervention to prevent the development and/or progression of OA in postmenopausal women. /the specific aims are to determine: 1) whether long-term ERT decreases the severity of OA in postmenopausal women. The specific aims are to determine: 1) whether long-term ERT decreases the severity of OA of the knee joints in surgically postmenopausal cynomolgus monkeys; 2) the effects of long-term ERT on the turnover and volume of the subchondral and epiphyseal/metaphyseal cancellous bone in the promisal tibia of surgically postmenopausal cynomolgus monkeys; and 3) the effects of estrogen on monkey articular caritlage matrix synthesis and degradation in vitro. Aims 1 and 2 will be accomplished through detailed morphologic examinations of knee joints collected at necropsy from a completed trial (30 months duration) designed to determine the effects of estrogens, progestogens, and tamoxifen on the extent of coronary artery atherosclerosis in surgically menopausal (bilaterally of ovariectomized) cynomolgus monkeys. In addition to morphological grading schemes and detailed histomorphometric analysis of articular cartilage and bone, tissue sections will be immunostained for specific biological markers of OA to evaluate the earliest possible morphological changes in articular cartilage in response to hormonal treatments. For aim 3, cell culture of chondrocytes isolated from normal articular cartilage obtained from adult female cynomolgus monkeys will be performed to examine the potential modulatory effects of estrogen on matrix synthesis and degradation. The effects of estrogen will be compared to those of progesterone and tamoxifen. These proposed studies provide a unique opportunity to obtain information which could support and provide mechanistic data for a full interventional study of ERT for the treatment of OA in humans.